Anaphylaxis and allergic reactions to COVID‐19 vaccines: A narrative review of characteristics and potential obstacles on achieving herd immunity

Abstract Background and Aims Coronavirus disease 2019 (COVID‐19) is a highly contagious infection, and new variants of its causative virus continue to emerge all around the world. Meanwhile, mass vaccination represents a highly effective measure to reduce the disease burden. Not only do vaccines immunize individuals, but they also protect the entire population through achieving herd immunity. They are composed of various ingredients, some of which may induce hypersensitivity reactions, namely anaphylaxis and cutaneous allergic reactions. This review aims to provide an explicit overview of the pathophysiology, suspected responsible components, and management of COVID‐19 vaccine‐induced allergic reactions, and their effect on acquiring herd immunity. Methods To perform this narrative review, a comprehensive literature search based on our selected terms was conducted in online databases of PubMed/Medline and Google Scholar for finding the relevant studies published from 2019 to 2022. Results COVID‐19 vaccines introduce several advantages that outweigh their potential risks, such as allergic reactions. Allergic reactions are mainly attributed to polyethylene glycol and polysorbate excipients that can provoke IgE‐mediated reactions and hypersensitivity reactions. These reactions should be managed properly to avoid having serious sequelae. Conclusion It is of great importance to immediately recognize and manage vaccine hypersensitivity reactions, especially anaphylaxis, to avoid allergic patients being excluded from the vaccination program, and more importantly, to stop the spreading of unfounded vaccine hesitancy leading to delayed herd immunity.


| INTRODUCTION
The ongoing coronavirus disease 2019 (COVID-19) pandemic induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has thus far infected nearly 220 million people and caused over 4.5 million deaths worldwide. Being highly contagious, COVID-19 has led to substantial changes in our lives, so many countries have struggled to find the optimal strategy for combating it. None of these approaches that range from precautionary measures to searching for efficacious treatment options have been as promising as the vaccination strategy. Mass vaccination is an encouraging cost-effective intervention to reduce morbidity and mortality, achieve herd immunity, and perhaps the most practical strategy to stop this pandemic.
Vaccination against COVID-19 represents an opportunity to retrieve normal conditions of life. Vaccines help develop immunity by imitating an infection and training lymphocytic cells to fight that disease in case of future invasion. 1 Not only do they immunize individuals, but they also protect the entire population by acquiring herd immunity. Vaccines have been applied as an effective public health intervention and have helped us dramatically improve human health and reduce the burden of infectious diseases since the mid-20th century. 2 However, as the body builds immunity, we can expect typical minor symptoms after vaccination, such as fever or fatigue. anaphylaxis, mainly in those with a history of allergies. 3 Despite being rare and uncommon, these reactions have given rise to hesitation in receiving the COVID-19 vaccine, which may delay achieving herd immunity towards this infection.
In this review, we provide an explicit overview of the pathophysiology of vaccine-induced allergic reactions and the so-far-reported allergic reactions to available COVID-19 vaccines. We also discuss their etiology, suspected responsible components, management, effect on vaccine hesitancy and aim to create a referable source for future studies. However, there is a limitation in comparing subcategories and different types of allergic reactions of each discussed vaccine in detail, as well as discussing allergic reactions to other available vaccines, both of which are due to the lack of sufficient clinical studies.

| METHODS
To perform this narrative review, we conducted a comprehensive literature search based on the selected terms including "COVID-19 vaccine," "allergic reaction," "hypersensitivity," "herd immunity," "anaphylaxis," "cutaneous reaction," "PEG," and "polysorbate." We explored online databases of PubMed/Medline and Google Scholar to find the relevant studies published from the emergence of

| Anaphylaxis as a life-threatening adverse reaction
Since the introduction of active vaccination against SARS-CoV2 and the beginning of vaccination campaigns, early safety monitoring has detected anaphylactic reactions that emerge after the injection of the first dose vaccine and resolve after treatment. 17 Anaphylaxis is a severe life-threatening systemic hypersensitivity reaction that occurs due to mast cell degranulation and the widespread release of mediators such as histamine. With a rapid onset, it usually occurs within minutes after the exposure to a specific allergen and is accompanied by airway constriction, circulatory problems, low level of consciousness, and may be associated with skin and mucosal changes. 18 Although anaphylactic reactions after vaccination are rare, they may be followed by serious complications. Thus, it is a matter of the utmost importance to identify and manage them quickly.
Most cases of anaphylactic reactions to COVID-19 vaccines have occurred in less than 30 min after vaccination via immediate IgE-mediated pathway in people with a history of allergic reactions, including anaphylaxis. 19 However, as is the case with any other medication, it is possible that anaphylactic reactions resulting from vaccination happen in the absence of a history of allergic diseases. 20 Regarding the epidemiology of these adverse events, reports imply that the overall occurrence of anaphylactic reactions due to COVID-19 vaccination, estimated at around 4.5 in a million, is higher than the expected rate of severe allergic reactions with an incidence of one in a million. 13,19,21,22 Furthermore, studies demonstrate that the rate of these reactions in women is higher than men, one reason of which could be the greater number of women who have been vaccinated during these observations. 19 Of note is that the incidence of adverse effects is lower with the Pfizer-BioNTech than with the Moderna vaccine. 23 A complete understanding of the underlying pathophysiology and the potential culprit of anaphylactic reactions to COVID-19 vaccines is yet to be determined. 24

| Cutaneous allergic reactions after administration of COVID-19 vaccines
Another reported allergic reaction to COVID-19 mRNA vaccines is dermatologic reactions, 25,26 some of which mimic the SARS-CoV2 infection itself, suggesting that the skin eruptions may be caused by immune activation rather than directly caused by the virus. 27 These reactions happen scarcely as a study reported their incidence 0.22% in vaccinated individuals and 16.54% of the whole vaccination adverse effects. 28 Their wide spectrum involves injection site reactions and more extensive reactions. They include the more common delayed large local reactions, localized redness and swelling, urticaria, maculopapular rashes, and the less common erythromelalgia, chilblains, cosmetic filler reactions, and pityriasis-rosea-like eruptions. A study showed that delayed large local reactions and urticaria were the most common cutaneous reactions following vaccination with Moderna and Pfizer-BioNTech, respectively. 29 Post-COVID vaccination facial swelling in people with previous use of cosmetic fillers was reported as a consequence of both mRNA vaccines. 29,30 It can be attributed to either immediate or delayed hypersensitivity reactions to filler ensuing from an immunogenic stimulus. [30][31][32] Delayed localized cutaneous reactions to COVID-19 in the injection site, called COVID arm or COVID vaccine arm, with a selflimiting course have been observed in vaccinated individuals. These reactions emerge on average 7 days after the first dose injection.
They can also appear after the second dose, though with a probability of less than 50%, faster development occurring in 2 days, and less for some other purposes. 12 Being present in small amounts, these components generally do not induce allergic reactions. Nevertheless, In patients with unusually high levels of IgE antibody and those who have a genetic predisposition to produce significantly high amounts of antibodies during exposure to several allergens, severe reactions, including anaphylaxis, can originate from very small amounts of antigens and develop. 11,35 In spite of the fact that mRNA vaccines are new, most of their components were used in other medications and cosmetic products previously, which multiplies the odds of causing sensitization in genetically predisposed patients. 36 Table 1 summarizes the main ingredients of mRNA-and vector-based COVID-19 vaccines as well as the incidence of anaphylactic reactions to each vaccine. 37 Since currently, our understanding of the exact underlying pathogenesis is unclear, an investigation has been launched into the inciting agents to improve our knowledge about these reactions and their culprit.
Polyethylene glycol (PEG), also known as macrogol, is a hydrophilic polyether polymer compound with variable chain length and a molecular weight that ranges from 20 to 10,000,000 g/mol.
PEGylation, the process in which PEGs bind to the systemic drugs, not only increases molecular weight and prolongs circulation time but also prevents the opsonization of the drug by shielding it from the immune system. 38 As PEGylation has been introduced as a technology that improves drug delivery, PEG is widely used as an excipient in various medications, cosmetics, and food products. Some of the pharmaceuticals that use this polymer-based drug delivery system are laxatives, penicillin, about 30% of tablets, chemotherapy drugs, and many injectable formulations. 39 In both Pfizer-BioNTech and Moderna mRNA vaccines, one of the excipients is PEG 2000, a PEG with a molecular weight of 2000 g/ mol. The modified mRNA used in these vaccines is easily taken up by mononuclear phagocytes, leading to rapid degradation by ribonucleases. Also, it has a poor penetration through the cell membrane originating from negative electric charge and high molecular weight.
Thus, needing a protective shield for being delivered to cells, it is formulated into LNPs that contain low levels of PEGylated lipids, for stabilizing the nanoparticle and increasing their solubility by enabling the assembly of a hydrate shell. 40  It has been speculated that PEGylated lipids are the potential allergic components and the culprit agent for the aforementioned hypersensitivity reactions to COVID-19 vaccines especially IgE-mediated anaphylaxis. Although PEG-containing products are generally considered safe, reports of IgE-mediated allergic reactions and anaphylaxis to PEGs of different molecular weights have been described in the literature. [42][43][44] There is difficulty in the assessment of anti-PEG IgE via skin testing as wheal and flare are not always produced in patients with true PEG allergies. 24,45 Because of this, hypersensitivity to PEG has been described as rare previously, yet there has been a surge in reports of allergic reaction to PEG in recent years, which is attributed to the increased administration of certain drugs or certain personal hygiene products. 38,46,47 A study has demonstrated that up to 70% of patients undergoing treatment with PEGylated products will develop anti-PEG IgG antibodies. 48 However, as mRNA vaccines use a novel technology and so far PEG has not been a common excipient in manufacturing vaccines, no reactions to the PEG-containing vaccines have been described previously. An explanation for how a patient may be sensitized to PEG before COVID-19 vaccination is their wide use in oral and injectable medications, cosmetics, and foods. 36 Allergic reactions to LNPs happen in case of previous exposure and antibody formation against a component of the LNP. The only component toward which anti-LNP antibodies have been detected in animal models and humans is the PEG polymer. 48 The exact molecular mechanism of these reactions in humans is not clearly understood and may involve IgE-and non-IgE-mediated immediate hypersensitivity reactions. 49   capacity for presentation to T cells. 50 There is a possibility that cross-reactivity happens between PEG and polysorbate80, another excipient in some vaccines, due to containing chemically common structures. 43 Polysorbate 80, also known as Tween 80, is another excipient that is contained in two vector-based COVID- 19

| Management and vaccination contraindications
Acute anaphylactic reactions occur without any strong correlation with age, sex, asthma, atopic status, or previous nonsevere reactions 52 and, in case of not being resolved, may cause severe sequels. Thus, it is necessary for all vaccination facilities to be equipped enough to immediately recognize and manage anaphylaxis.
It is of great importance to take the background allergic history of individuals thoroughly to determine whether COVID-19 vaccination is contraindicated in them or not. One of the points to be aware of is a history of mild or severe allergic reactions, especially to PEGor polysorbate-containing products. 53 It has been suggested that individuals with a history of allergic reactions due to any cause should be monitored for 30 min after COVID-19 vaccination. 12  into contact with a susceptible person. 56 Although achieving herd immunity through vaccination would considerably help control the disease, it will not end the pandemic. 57 Eradication of the smallpox virus by global mass vaccination is a good showcase for vaccinationinduced herd immunity. In this respect, immunization of more than 80% of the global population against the virus decreased the number of susceptible hosts to lower than the threshold needed for transmission. 58 The World Health Organization estimates that global vaccination programs save 2-3 million lives per year. 59 It is assumed that for the induction of herd immunity against COVID-19, a protective immunity rate of approximately 60% of the total population is required. 60 There are several factors that form the compliance of citizens with vaccination strategy and their confidence in vaccines. One of these factors is the public knowledge about the mechanism and benefits of achieving herd immunity. 61 Other factors range from awareness in society about vaccines and their possible associated risks to religious, political, social, and economic status. Figure 1 shows the main factors that increase or decrease vaccine acceptability which has a strong association with herd immunity. Meanwhile, The corresponding author had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

ACKNOWLEDGMENTS
No funding was received to assist with the preparation of this manuscript.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

TRANSPARENCY STATEMENT
The lead author (Nima Rezaei) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
F I G U R E 1 Key factors affecting vaccine acceptability and the journey to reach herd immunity. There are several positive and negative contributors to vaccine acceptability among people, an important factor of which is the history of pre-existing allergic diseases and fear of severe reactions to vaccine components. The resultant vaccine acceptability rate determines the time of achieving herd immunity, the advantages of which involve social, health, and economic aspects ORCID Sara Mahdiabadi http://orcid.org/0000-0002-9502-2717 Nima Rezaei http://orcid.org/0000-0002-3836-1827